Several dry powder technologies, including lactose carrier particle blends, porous particles, and active inhaler (e.g., to deliver poorly dispersible powders), for delivery of therapeutic agents to the respiratory track exist, but each have limitations.
Lactose carrier particle blends use relatively large lactose particles, e.g. 40 micrometers to 250 micrometers, as a means of deagglomeration and aerosolization of micronized therapeutic agent. This leads to 1) dry powder formulations that have a low amount of therapeutic agents per unit of powder volume, and 2) dry powder formulations in which a relatively high percent of the therapeutic agent in the formulation adheres to and does not separate from the lactose carrier before the lactose carrier impacts the back of the patient's throat during inhalation and is swallowed. This latter point leads to high loss of therapeutic agent that never reaches the respiratory tract, thus requiring a significantly higher nominal dose to be administered than would otherwise be needed. The impaction in the upper throat can lead to hoarseness and oropharyngeal candidiasis, especially for corticosteroids. Additionally, digestion or exposure to therapeutic agents in the gastrointestinal tract leads to increased chance of undesired side effects. A third disadvantage to lactose blends is that the variety of therapeutic agents that are compatible with lactose blends is limited. It is well known that in general drugs should be crystalline when formulated with lactose blends. A fourth disadvantage of the lactose blending technology is that it has proven difficult to maintain uniform dosing to different areas of the respiratory tract, especially when the dry powder includes more than one therapeutic agent e.g., double and especially triple combinations. This is due to the fact that the various therapeutic agents are simply blended with the lactose, but the therapeutic agents are also bound to each other (e.g., homotypic and heterotypic binding), thus potentially resulting in different therapeutics depositing at different sites in the respiratory tract.
Porous particles tend to produce relatively homogenous dry powders. However, due to the porous nature of the powder, e.g., tap density of less than 0.4 g/cm3, and often about 0.1 g/cm3, the mass density and therefore therapeutic density, the amount of therapeutic agent per unit volume of powder, is also low. This means that in general a relatively large volume of dry particles that are porous is required to deliver an effective dose of therapeutic agent. A second drawback of porous particles in that they have poor processability. In fact, it is so difficult to process porous particles that primarily capsule-based technologies have been promoted in the attempt to commercialize porous particle platforms for therapeutic drug delivery. Some processability problems the porous particles face include, e.g., 1) bridging of the particles, e.g., across the opening of a receptacle, which limits the ability to fill receptacles with the dry powders for storage, distribution and/or dosing; across the receptacle, and 2) a tendency of the porous particles to aerosolize during filling processes and not settle into the desired receptacle for storage, distribution and later dosing.
Active inhalers use an energy source, other than the patient's breathing, to disperse the dry powder during administration. With this approach, poorly dispersible powders, such as micronized therapeutic agents, should be suitably dispersed for administration to the lungs. Although these devices held a lot of promise based on the theory of their operation, in practice they have not lived up to this promise. Due to their highly technical design, often including electronic circuitry, active inhalers have shown poor durability in tests that simulate ordinary wear and tear. Some active inhalers have used large volumes to disperse the dry powder, such as Nektar's Exubera device. However, the relatively large size of such devices is undesired by patients, and potentially leads to poor patient compliance.
There is a need for improved dry powder technology.